| First Author | Jansen MI | Year | 2025 |
| Journal | Life Sci | Volume | 378 |
| Pages | 123843 | PubMed ID | 40628313 |
| Mgi Jnum | J:374214 | Mgi Id | MGI:8259277 |
| Doi | 10.1016/j.lfs.2025.123843 | Citation | Jansen MI, et al. (2025) Neuronal PAC1 deletion impairs structural plasticity. Life Sci 378:123843 |
| abstractText | AIMS: Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is an endogenous neuropeptide of the central nervous system (CNS), whose biological activities are mediated via three G protein-coupled receptors PAC1, VPAC1, and VPAC2. While its neuroprotective functions are well-characterised, the role of PAC1 receptor-specific signalling in neuronal plasticity remains insufficiently understood. This study aimed to define the contribution of PAC1 signalling in excitatory pyramidal neurons across brain regions critical for cognitive and motor functions. MATERIALS AND METHODS: We employed a tamoxifen-inducible, conditional knockout mouse model to delete the PAC1 receptor gene (Adcyap1r1) specifically in Camk2a-expressing excitatory neurons. The model was crossed with Thy1-YFP and Thy1-mitoCFP reporter lines to enable high-resolution imaging of neuronal structures and mitochondria in the cortex and hippocampus. Behavioural assessments, molecular analyses, and confocal imaging were conducted to evaluate structural, functional, and biochemical consequences of PAC1 deletion. KEY FINDINGS: Loss of PAC1 in Camk2a(+) neurons resulted in spatial memory deficits and locomotor impairments. These were associated with elevated expression of neuronal nitric oxide synthase (nNOS) and GAD65/67, reduced CREB phosphorylation at Ser133, diminished dendritic spine density, and decreased mitochondrial content. The most pronounced effects were observed in the CA1 region of the hippocampus. SIGNIFICANCE: Our findings establish PAC1 as a key modulator of synaptic integrity, neuronal plasticity, and energy homeostasis in excitatory neurons. These insights underscore PAC1's potential as a therapeutic target in neurological disorders characterised by cognitive decline and synaptic dysfunction. |
